More patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease than direct pulmonary complications. Inflammation and oxidative stress, characteristic in COPD, are likely contributors to the reduction in nitric oxide (NO) bioavailability and vascular endothelial dysfunction in COPD patients; however, this has yet to be determined. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in contributing to vascular endothelial dysfunction in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress, both independently, contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD.

Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following an increase in nitric oxide bioavailability (BH4).

Drug: Tetrahydrobiopterin (BH4)

single dose = 5 mg/kg

Other Name: Kuvan (Sapropterin Dihydrochloride)

Experimental: Decrease in NO Bioavailability

Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following a decrease in nitric oxide bioavailability (high fat meal).

Dietary Supplement: High Fat Meal

The high-fat meal ([900 calories], 50 g of fat, 14 g of saturated fat, 225 mg of cholesterol) will consist of an Egg McMuffin®, Sausage McMuffin®, and two hash brown patties (McDonald's Corporation®). Additional water will be allowed ad libidum. The P.I. along with others have used this meal to attenuate FMD in healthy adults with the mechanism suggested to be through an increase in lipemia induced oxidative stress.

Experimental: Inhibition of NO

Brachial artery flow-mediated dilation (FMD), markers of inflammation, and markers of oxidative stress will be assessed at baseline and following competitive inhibition of nitric oxide production (L-NMMA).

Drug: L-NMMA

dosage range = 4 mg/kg/min

Experimental: Inhibition of Inflammation

Brachial artery flow-mediated dilation and biomarkers of inflammation (IL-6, IL-1β, TNF-α, NF-kβ) will be assessed at baseline and following 4 days of therapeutic doses (3,000 mg per day) of Salsalate (non-acetylated salicylate) treatment or placebo. This treatment dose is the standard therapy prescribed for patients with inflammatory arthritis.

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01398943